This invention relates to a method of inhibiting the production of cytokines, particularly inhibiting the production of interleukin-1 and inhibiting the production of tumor necrosis factor, in a mammal, including a human, in need thereof which comprises administering to such mammal an effective, cytokine production inhibiting amount of a substituted azaspirane.
Badger et al., U.S. Pat. No. 4,963,557 issued Oct. 16, 1990, discloses compounds of the formula ##STR1## wherein: n is 3-7; m is 1 or 2; R.sub.1 and R.sub.2 are the same or different and are selected from hydrogen or straight chain, branched chain or cyclic alkyl, provided that the total number of carbon atoms contained by R.sub.1 and R.sub.2 when taken together is 5-10; or R.sub.1 and R.sub.2 are joined together to form a cyclic alkyl group having 3-7 carbon atoms; R.sub.3 and R.sub.4 are the same or different and are selected from hydrogen or straight chain alkyl having 1-3 carbon atoms; or R.sub.3 and R.sub.4 are joined together with the nitrogen atom to form a heterocyclic group having 5-8 atoms; or a pharmaceutically acceptable salt or hydrate or solvate thereof. Badger et al., also discloses that such compounds have utility in inducing immune suppression via induction of suppressor cell like activity based on their activity in the adjuvant-induced arthritis test in rats and their activity in the suppressor cell assay. The adjuvant arthritis test is useful for detecting compounds which are inhibitors of prostanoid synthesis, but is of no utility for disclosing or suggesting compounds which are inhibitors of cytokine production, particularly compounds which are inhibitors of interleukin-1 (IL-1) and/or tumor necrosis factor (TNF). The suppressor cell assay is useful for detecting immunosuppressive compounds but is of no known utility for disclosing or suggesting compounds which are inhibitors of cytokine production, particularly compounds which are inhibitors of IL-1 and/or TNF production.
Cytokines are biological substances produced by a variety of cells, such as monocytes or macrophages. Cytokines affect a wide variety of cells and tissues and are important and critical inflammatory mediators of a wide variety of disease states and conditions. The inhibition of these cytokines is of benefit in controlling, reducing and alleviating many of these disease states.